TSLP (thymic stromal lymphopoietin) and TL1A (Tumor necrosis factor-like cytokine 1A) have emerged as game-changers in treating immune-mediated inflammation diseases (IMIDs). This review explores the biological activities of TSLP and TL1A, their significance in asthma and Crohn's disease, and recent breakthroughs in drug development. Discover why they are creating a buzz for biopharmas and shaping the future of personalized medicine.
The quest for new therapeutic targets
Increased cytokine levels in serum often indicate an ongoing immune response to fight infections or malignancies. However, elevated cytokines can also reflect dysregulated immune responses, leading to inflammatory and autoimmune disorders. The development of recombinant monoclonal antibodies (mAbs) and in vivo mouse disease models has made it easier to identify and manipulate important cytokine(s) as potential therapeutic targets. Today, more than 30 therapeutic mAbs neutralizing cytokines or their receptors have been authorized to treat IMIDs (e.g. Crohn’s disease, asthma, atopic dermatitis, rheumatoid arthritis, lupus)1. However, long-term cytokine suppression, such as TNF-α or
IL-4-targeting strategies, can lead to side effects or ineffective treatment for many individuals2, 3.
Why are TSLP and TL1A promising targets?
The lack of complete efficacy for current therapeutics may be explained by the fact that they target individual, downstream elements of the inflammatory cascade. TSLP and TL1A stand out as they are upstream elements, acting at the early stages of inflammation. Targeting these cytokines offers a strong twofold advantage:
- Modulating cytokines upstream rather than downstream can help achieve broader and more effective management of inflammation.
- This approach also significantly improves the likelihood of preventing dysregulated immune responses, lowering symptom exacerbation.
The biopharma industry is now setting its sights on TSLP and TL1A, particularly for severe asthma and Crohn’s disease. The race is on to produce effective blocking mAbs:
- TSLP-neutralizing Tezepelumab was approved by the FDA in 2021 for severe asthma4. Other biologics are still in clinical development, such as AZD8630/AMG104, an inhaled anti-TSLP mAb, or Verekitug, an anti-TSLP receptor mAb5.
- TL1A-neutralizing Tulisokibart and Duvakitug, are currently undergoing phase II/III clinical trials for IBD (Crohn’s disease and ulcerative colitis)6-8. Duvakitug is also being studied for its safety as an asthma therapy9, 10.
What are the functions of TSLP and TL1A?
TSLP and TL1A exert a common alarmin cytokine function11. They are rapidly released from epithelial cells upon infection, allergen exposure, or mechanical injury to induce and propagate inflammation.
- TSLP belongs to the common γ chain (γc) cytokine family and is primarily produced by epithelial and stromal cells in barrier tissues, (lungs, skin, and gastrointestinal tract). It is also produced by innate cells like dendritic cells (DCs), basophils, and mast cells12. TSLP binds to a heterodimeric transmembrane receptor comprising the IL-7Rα and TSLPR chains. It signals through tyrosine kinases of the Janus family (JAK1, JAK2) and signal transducer and transcription activators (STATs), notably STAT512. TSLP is a critical mediator of type 2 (T2) immune responses, characterized by the release of IL-4, IL-5, IL-13, IL-17A, and IL-22 cytokines. It acts through DC maturation, Th2 and Th17 subsets polarization, as well as activation of group 2 innate lymphoid cells (ILC2s)11-13.
- TL1A is a trimeric molecule belonging to the tumor necrosis factor (TNF) superfamily. It is produced in endothelial cells, activated DCs, and macrophages. It can exist in both membrane-bound and soluble forms14. TL1A binds to a homotrimeric transmembrane death receptor 3 (DR3), or to its soluble decoy counterpart (DcR3). It triggers NF-κB and MAPKs activation to induce inflammatory gene expression. Alternatively, it can trigger caspase-8 activation, resulting in cell death14. TL1A provides a co-stimulatory signal to T cells, influencing their differentiation into Th1, Th2, and Th17 cells14, 15. While Th17 and Th2 cells mainly produce T2 cytokines, Th1 essentially secrete IFN-γ and TNF-α14. TL1A/DR3 signaling also promotes ILC2s to proliferate and produce large amounts of IL-5, IL-13, and transiently IL-911, 14, 15. TL1A dual signaling capabilities can also induce apoptosis in certain contexts, highlighting its complex role in immune regulation14.
Overall, although they do not bind to receptors of the same family nor signal through identical pathways, TSLP and TL1A display redundancy in their immune functions. This ensures that the immune system continues to operate even when one cytokine is lacking or compromised.
Interestingly, TSLP appears to perform a role upstream of TL1A in ILC2s. In the context of allergic airway inflammation, TSLP induces ILC2s to upregulate DR3 cell-surface expression, thereby exacerbating inflammatory responses11, 16. Whether this cooperation holds for other diseases remains to be investigated.
How do TSLP and TL1A contribute to asthma & Crohn’s disease?
TSLP and TL1A mediate early protective immune responses. However, they can also contribute negatively to chronic inflammatory disorders, including asthma and Crohn's disease. They do so by:
- Genetic predisposition: TSLP and TL1A polymorphisms have
been linked to disease susceptibility and severity11, 12. - Overactivation of downstream actors: Their target cells foster persistent local inflammation and immune cell infiltration, contributing to tissue damage14, 18.
- TSLP and TL1A impact in asthma: TSLP and TL1A stimulate the production of T2 cytokines by lung-resident immune cells, notably ILC2s, Th2, and Th17 cells3, 11, 16, 18. These T2 cytokines drive lung eosinophilia, mucus overproduction, and airway hyperresponsiveness.
- TL1A impact in Crohn’s disease: TL1A alters the epithelial-mesenchymal transition, resulting in colonic fibrosis and inflammatory reactions14. TL1A also increases the production of IFN-γ and TNF-α by Th1 cells, and IL-17 by Th17 cells, exacerbating intestinal inflammation14, 17.
TSLP and TL1A drug development
Pharmaceutical companies have developed potent mAbs to block TSLP or TL1A signaling and stop the downstream inflammatory cascade in the setting of asthma and IBD.
- Amgen's Tezepelumab (AMG157) is the only anti-TSLP antibody currently licensed for treating severe asthma3-5. This drug stands out among the panels of asthma treatments as it improves clinical outcomes in all asthma endotypes. Importantly, Tezepelumab can modulate airway inflammation that is not controlled with biologics that block specific downstream elements of the inflammatory cascade (e.g. anti-IL-4/13 receptor antibody Dupilumab, inhaled corticosteroids)4. Tezepelumab is being tested in clinical trials for many illnesses, including chronic rhinosinusitis, chronic obstructive pulmonary disease, and chronic spontaneous urticaria12. The TSLP-based therapeutic landscape is still expanding, with numerous biologics in the preclinical or clinical development stages. These include mAbs neutralizing TSLP (e.g., AZD8630) or TSLP receptor (Verekitug), as well as a small chemical inhibitor, BP79, targeting the TSLP receptor5.
- Anti-TL1A inhibitors such as Tulisokibart (MK-7240 or PRA023), RVT-3101 (PF-06480605), and Duvakitug (TEV-48574) have demonstrated "best-in-class" potential for treating inflammation and scarring in IBD6-8. Duvakitug is currently being studied for its safety as an asthma medication9, 10.
Stopping the “atopic march”
As the incidence of allergic diseases continues to rise worldwide, strong efforts are being made to understand the mechanisms underlying these conditions for better prevention and control. The concept of “atopic march” is based on studies suggesting that allergic diseases manifest gradually and sequentially: from atopic dermatitis and food allergy in infancy to allergic asthma and allergic rhinitis in childhood19. TSLP and TL1A, along with other alarmins found in the skin, gastrointestinal tract, and lungs, may be useful biomarkers for predicting the “atopic march”. Future research could lead to the development of tailored treatments based on therapies that block alarmins locally (topical, oral, or inhalation delivery) and temporally (during infancy or youth).
Overall, the upstream positioning of TSLP and TL1A in the inflammation cascade in IMIDs makes them attractive pharmacological targets. According to available data, biopharma is now focusing a lot of work on TSLP and TL1A to enhance current treatments and break through the efficacy ceiling associated with current top medications on the market.
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